Excess TGF beta in neonatal lung injury and repair

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DESCRIPTION (provided by applicant): Hypothesis: The TGFbeta signaling pathway may function as a final common pathway to mediate the negative impact of neonatal lung injury on alveolar formation and gas exchange. Aim 1. Candidate gene induction: to determine the impact of neonatal hyperoxia and/or LP5 endotoxin, on time and space-specific expression and activity of TGFbeta ligand, cognate receptor and cognate Smad (2,3 and 4) expression in neonatal mouse lung. Aim 2. Candidate gene function: to compare the impact of neonatal hyperoxia and/or LP5 endotoxin, versus local overexpression of IL1-beta, or TNF-alpha, with that of TGF-beta1 using recombinant adenoviral vectors to determine which of them also phenocopies BPD by abrogation of alveolarization. Aim 3. Smad3 as a common downstream gene: to discover which effects of neonatal hyperoxia and/or LPS endotoxin injury, IL1beta, TNFalpha, and/or TGFbeta1 signaling in neonatal lung are transduced through a common TGF-alpha/Smad3 signaling pathway, using the Smad3 null mouse as a test model. Aim 4. Protection: to determine whether the negative sequelae of neonatal hyperoxia and/or LP5 endotoxin injury on alveolar formation can be blocked or ameliorated, either upstream or downstream within the TGF-beta pathway using recombinant viruses expressing Decorin or Smad7. Health Significance: we postulate that blocking key upstream inducers of TGFabeta signaling, correctly modulating TGFbeta signaling and/or inhibiting the downstream effects of TGFbeta could prevent or ameliorate alveolar hypoplasia/BPD.